Clinical features and literature review of 4 cases of <i>DNA A3243G</i> mutation-related MELAS syndrome_Journal of Epilepsy

Authors：

FENG Jie ,  GAO LI , REN Chunming , YIN Xiaojing , LI Yan , FAN HONG Ye , QI Hui , YANG Liu

Departmentof Neurology, General Hospital of Henan Province, Zhengzhou 4530003, China;

Corresponding author：

GAO LI, Email: 1879872583@qq.com

Keywords：

MELAS syndrome; clinical features; DNA A3243G mutation; Genetics analysis therapy

DOI：

10.7507/2096-0247.20190070

Video：

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Objective To investigate the clinical characteristics and genetic phenotype of mitochondrial myopathy associated with lactic acidemia and stroke-like seizure syndrome (MELAS) in DNA A3243G mutation, and to improve the clinical understanding and diagnosis.Methods The clinical data and imaging characteristics of 4 patients with DNA A3243G mutation-related MELAS syndrome who were diagnosed and treated in the Department of Pediatric Neurology, Henan Provincial People's Hospital from June 2017 to June 2018 were retrospectively reviewed.Results Of the 4 patients, 3 were caused by convulsions, 1 was caused by dizziness, and the MELAS syndrome caused by mitochondrial DNA A3243G mutation was confirmed by genetic testing. The patients were treated with anti-epilepsy drugs. The patients were followed up for at least 1 year, and 2 of 4 patients were stable, 1 patient still had seizures, and 1 patient did not improved.Conclusions The clinical phenotypic heterogeneity of patients with DNA A3243G mutation-related MELAS syndrome is caused by the " heterogeneity” and " threshold effect” of DNA mutation. The mutation rate of DNA A3243G is as high as 80%. In the era of promoting precision medicine, genes examination can help early diagnosis and early treatment of MELAS syndrome as well as improve the quality of life of patients and improve the prognosis.

Citation： FENG Jie, GAO LI, REN Chunming, YIN Xiaojing, LI Yan, FAN HONG Ye, QI Hui, YANG Liu. Clinical features and literature review of 4 cases of DNA A3243G mutation-related MELAS syndrome. Journal of Epilepsy, 2019, 5(6): 440-444. doi: 10.7507/2096-0247.20190070 Copy

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2.	Rötig, A. Human diseases with impaired mitochondrial protein synthesis. BiochimBiophys Acta, 2011, 1807(9): 1198-205.
3.	DiMauro S, Schon EA, Carelli V. The clinical maze of mitochondrial eurology. Nat Rev Neurol, 2013, 9(8): 28-44.
4.	Boczonadi V, Horvath R. Mitochondria: impaired mitochondrial translation in human disease. Int J Biochem Cell Biol, 2014, 48: 77-84.
5.	Pavlakis SG, hillips PC, DiMauro S. Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke like episodes: a distinctive clinical syndrome. Ann Neurol, 1984, 16(4): 481-488.
6.	Pankuweit S, Richter A. Mitochondrial disorders with cardiac dysfunction: an under-reported aetiology with phenotypic heterogeneity. Eur Heart J, 2015, 36(42): 2894-2897.
7.	El-Hattab AW, Almannai M, Scaglia F. MELAS. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Stephens K, Amemiya A, editors. GeneReviews. Seattle (WA): University of Washington, Seattle; 1993-2019.
8.	Li X, Wang Y, Wang Z. Comparison of magnetic resonance spectroscopy (MRS) with arterial spin labeling (ASL) in the differentiation between mitochondrial encephalomyopathy, lactic Acidosis, plus stroke-like episodes (MELAS) and acute ischemic stroke (AIS). J Clin Neurosci, 2018, 55: 65-70.
9.	Yeo BT, Eickhoff SB. Systems neuroscience: a modern map of the human cerebral cortex. Nature, 2016, 536(7615): 15215-15224.
10.	Glasser MF, Coalson TS, Robinson EC, et al. A ulti-modal parcellation of human cerebral cortex. Nature, 2016, 536(7615): 171-178.
11.	Bellani M, Boschello F, Delvecchio G, et al. DTI and myelin plasticity in bipolar disorder: integrating neuroimaging and neuropathological findings. Front Psychiatry, 2016, 7(1): 21.
12.	AurangzedS, Vale T, Tofairs G. Mitochondrial encephalomyopathy with acidosis and stoke-like episodes (MELAS) in the oder adult. Pract Neurol, 2014, 14(6): 432-436.
13.	修建军, 李传福, 张金山, 等. MELAS 综合征的 MRI 表现. 实用放射学杂志, 2008, 24(10): 1317-1319.
14.	Nishigaki Y, Fuku N, Tanaka M. Mitochondrial dysfunctions and age-associated diseases. Nihon Ronen lgakkai Zasshi, 2006, 43(3): 274-282.
15.	Goto Y, Nonaka I, Horai S. A mutation in the tRNA(Leu)(UUR) gene associated with the MELAS subgroup of mitochondrial encephalomyopathies. Nature, 1990, 348(6302): 651-653.
16.	Kadowaki T, Kadowaki H, Mori Y, et al. A subtype of diabetes mellitus associated with a mutation of mitochondrial DNA. N Engl J Med, 1994, 330(14): 962-968.
17.	van den Ouweland JM, Lemkes HH, Ruitenbeek W, et al. Mutation in mitochondrial tRNA(Leu)(UUR) gene in a large pedigree with maternally transmitted type II diabetes mellitus and deafness. Nat Genet, 1992, 1(5): 368-371.
18.	Finsterer J. Genetic, pathogenetic, and phenotypic implications of the mitochondrial A3243G tRNALeu(UUR) mutation. Acta Neurol Scand, 2007, 116(1): 1-14.
19.	Goodfellow JA, Dani K, Stewart W, et al. Mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes: an important cause of stroke in young people. Postgrad Med J, 2012, 88(1040): 326-334.
20.	Uusimaa J, Moilanen JS, Vainionpaa L, et al. Prevalence, segregation, and phenotype of the mitochondrial DNA 3243A>G mutation in children. Ann Neurol, 2007, 62(3): 278-287.
21.	Jiang TES, Kauppila E, Motori M, et al. Increased Total mtDNA copy number cures male infertility despite unaltered mtDNA mutation load. Cell Metab, 2017, 26(2): 429-436.
22.	DiFrancesco JC, Cooper JM, Lam A, et al. MELAS mitochondrial DNA mutation A3243G reduces glutamate transport in cybrids cell lines. Exp Neurol, 2008, 212(1): 152-153.
23.	万方, 马炜楠, 王晓慧, 等. 线粒体脑肌病伴乳酸血症和卒中样发作综合征的临床特征及遗传学研究. 中国循证儿科杂志, 2008, 5(3): 169-172.
24.	Ma H, Folmes CD, Wu J, et al. Metabolic rescue in pluripotent cells from patients with mtDNA disease. Nature, 2015, 524(7564): 234-238.
25.	吴洵昳, 朱国行, 王晋扬, 等. 以癫痫持续状态起病的线粒体脑病合并乳酸血症与脑卒中样发作的临床特征分析. 中国临床神经科学, 2012, 20(1): 37-42.
26.	Finsterer J. Stroke and Stroke-like episodes in muscle disease. Open Neurol J, 2012, 6(2): 26-36.
27.	Koga Y, Akita Y, Junko N, et al. Endothelial dysfunction in MELAS improved by Larginine supplemention. Neurology, 2006, 66(11): 1766-1769.
28.	Finsterer J, Wakil SM. Stroke-like episodes, peri-episodic seizures, and MELAS mutations. Eur J Paediatr Neurol, 2016, 20(6): 824-829.
29.	Yuen AWC, Walcutt IA, Sander JW. An acidosis-sparing ketogenic (ASK) diet to improve effcacy and reduce adverse effects in the treatment of refractory epilepsy. Epilepsy Behav, 2017, 74(9): 15-21.
30.	Craven L, Tuppen HA, Gregains GD, et al. Pronuclear transfer in human embryos to prevent transmission of mitochondrial DNA disease. Nature, 2010, 465(7294): 82-85.

1. Chandel NS. Mitochondria as signaling organelles. BMC Biol, 2014, 27(12): 34.
2. Rötig, A. Human diseases with impaired mitochondrial protein synthesis. BiochimBiophys Acta, 2011, 1807(9): 1198-205.
3. DiMauro S, Schon EA, Carelli V. The clinical maze of mitochondrial eurology. Nat Rev Neurol, 2013, 9(8): 28-44.
4. Boczonadi V, Horvath R. Mitochondria: impaired mitochondrial translation in human disease. Int J Biochem Cell Biol, 2014, 48: 77-84.
5. Pavlakis SG, hillips PC, DiMauro S. Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke like episodes: a distinctive clinical syndrome. Ann Neurol, 1984, 16(4): 481-488.
6. Pankuweit S, Richter A. Mitochondrial disorders with cardiac dysfunction: an under-reported aetiology with phenotypic heterogeneity. Eur Heart J, 2015, 36(42): 2894-2897.
7. El-Hattab AW, Almannai M, Scaglia F. MELAS. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Stephens K, Amemiya A, editors. GeneReviews. Seattle (WA): University of Washington, Seattle; 1993-2019.
8. Li X, Wang Y, Wang Z. Comparison of magnetic resonance spectroscopy (MRS) with arterial spin labeling (ASL) in the differentiation between mitochondrial encephalomyopathy, lactic Acidosis, plus stroke-like episodes (MELAS) and acute ischemic stroke (AIS). J Clin Neurosci, 2018, 55: 65-70.
9. Yeo BT, Eickhoff SB. Systems neuroscience: a modern map of the human cerebral cortex. Nature, 2016, 536(7615): 15215-15224.
10. Glasser MF, Coalson TS, Robinson EC, et al. A ulti-modal parcellation of human cerebral cortex. Nature, 2016, 536(7615): 171-178.
11. Bellani M, Boschello F, Delvecchio G, et al. DTI and myelin plasticity in bipolar disorder: integrating neuroimaging and neuropathological findings. Front Psychiatry, 2016, 7(1): 21.
12. AurangzedS, Vale T, Tofairs G. Mitochondrial encephalomyopathy with acidosis and stoke-like episodes (MELAS) in the oder adult. Pract Neurol, 2014, 14(6): 432-436.
13. 修建军, 李传福, 张金山, 等. MELAS 综合征的 MRI 表现. 实用放射学杂志, 2008, 24(10): 1317-1319.
14. Nishigaki Y, Fuku N, Tanaka M. Mitochondrial dysfunctions and age-associated diseases. Nihon Ronen lgakkai Zasshi, 2006, 43(3): 274-282.
15. Goto Y, Nonaka I, Horai S. A mutation in the tRNA(Leu)(UUR) gene associated with the MELAS subgroup of mitochondrial encephalomyopathies. Nature, 1990, 348(6302): 651-653.
16. Kadowaki T, Kadowaki H, Mori Y, et al. A subtype of diabetes mellitus associated with a mutation of mitochondrial DNA. N Engl J Med, 1994, 330(14): 962-968.
17. van den Ouweland JM, Lemkes HH, Ruitenbeek W, et al. Mutation in mitochondrial tRNA(Leu)(UUR) gene in a large pedigree with maternally transmitted type II diabetes mellitus and deafness. Nat Genet, 1992, 1(5): 368-371.
18. Finsterer J. Genetic, pathogenetic, and phenotypic implications of the mitochondrial A3243G tRNALeu(UUR) mutation. Acta Neurol Scand, 2007, 116(1): 1-14.
19. Goodfellow JA, Dani K, Stewart W, et al. Mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes: an important cause of stroke in young people. Postgrad Med J, 2012, 88(1040): 326-334.
20. Uusimaa J, Moilanen JS, Vainionpaa L, et al. Prevalence, segregation, and phenotype of the mitochondrial DNA 3243A>G mutation in children. Ann Neurol, 2007, 62(3): 278-287.
21. Jiang TES, Kauppila E, Motori M, et al. Increased Total mtDNA copy number cures male infertility despite unaltered mtDNA mutation load. Cell Metab, 2017, 26(2): 429-436.
22. DiFrancesco JC, Cooper JM, Lam A, et al. MELAS mitochondrial DNA mutation A3243G reduces glutamate transport in cybrids cell lines. Exp Neurol, 2008, 212(1): 152-153.
23. 万方, 马炜楠, 王晓慧, 等. 线粒体脑肌病伴乳酸血症和卒中样发作综合征的临床特征及遗传学研究. 中国循证儿科杂志, 2008, 5(3): 169-172.
24. Ma H, Folmes CD, Wu J, et al. Metabolic rescue in pluripotent cells from patients with mtDNA disease. Nature, 2015, 524(7564): 234-238.
25. 吴洵昳, 朱国行, 王晋扬, 等. 以癫痫持续状态起病的线粒体脑病合并乳酸血症与脑卒中样发作的临床特征分析. 中国临床神经科学, 2012, 20(1): 37-42.
26. Finsterer J. Stroke and Stroke-like episodes in muscle disease. Open Neurol J, 2012, 6(2): 26-36.
27. Koga Y, Akita Y, Junko N, et al. Endothelial dysfunction in MELAS improved by Larginine supplemention. Neurology, 2006, 66(11): 1766-1769.
28. Finsterer J, Wakil SM. Stroke-like episodes, peri-episodic seizures, and MELAS mutations. Eur J Paediatr Neurol, 2016, 20(6): 824-829.
29. Yuen AWC, Walcutt IA, Sander JW. An acidosis-sparing ketogenic (ASK) diet to improve effcacy and reduce adverse effects in the treatment of refractory epilepsy. Epilepsy Behav, 2017, 74(9): 15-21.
30. Craven L, Tuppen HA, Gregains GD, et al. Pronuclear transfer in human embryos to prevent transmission of mitochondrial DNA disease. Nature, 2010, 465(7294): 82-85.

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